Pyridines reactivity toward electrophiles

Despite its V excessive character (340), thiazole, just as pyridine, is resistant to electrophilic substitution. In both cases the ring nitrogen deactivates the heterocyclic nucleus toward electrophilic attack. Moreover, most electrophilic substitutions, which are performed in acidic medium, involve the protonated form of thiazole or some quaternary thiazolium derivatives, whose reactivity toward electrophiles is still lower than that of the free base. 

There is another important factor in the low reactivity of pyridine derivatives toward electrophilic substitution. The —N=CH— unit is basic because the electron pair on nitrogen is not part of the aromatic n system. The nitrogen is protonated or complexed with a Lewis acid under many of the conditions typical of electrophilic substitution reactions. The formal positive charge present at nitrogen in such species further reduces the reactivity toward electrophiles. 

For pyridine, the reactivity toward electrophilic substitution is 3 > 4, 2. The ring nitrogen acts as a strongly destabilizing internal electron-withdrawing substituent in the 2- and 4-intermediates. The nitrogen also deactivates the 3-position, but less so than the 2- and 4-positions. 

This improves reactivity towards electrophiles. Consideration of resonance structures shows positions 2, 4, and 6 are now electron rich. Nitration of pyridine A-oxide occurs at C-4 very little 2-nitration... 

Quinoline is much more reactive towards electrophilic substitution than pyridine, but this is because substitution occurs on the benzene ring, not on the pyridine. We have already seen that pyridine carbons are unreactive towards electrophilic reagents, with strongly acidic systems protonating the nitrogen... 

Problem 20.22 Compare, and explain the difference between, pyridine and pyrrole with respect to reactivity toward electrophilic substitution. 

Like 1,3-azoles, due to the presence of a pyridine-like nitrogen atom in the ring, 1,2-azoles are also much less reactive towards electrophilic substitutions than furan, pyrrole or thiophene. However, 1,2-azoles undergo electrophilic substitutions under appropriate reaction conditions, and the main substitution takes place at the C-4 position, for example bromination of 1,2-azoles. Nitration and sulphonation of 1,2-azoles can also be carried out, but only under vigorous reaction conditions. 

Electrophilic aromatic substitutions The chemistry of pyrimidine is similar to that of pyridine with the notable exception that the second nitrogen in the aromatic ring makes it less reactive towards electrophilic substitutions. For example, nitration can only be carried out when there are two ring-activating substituents present on the pyrimidine ring (e.g. 2,4-dihydroxypyrimidine or uracil). The most activated position towards electrophilic substitution is C-5. 

It is convenient to consider heteroaromatic ligands in two classes - 7t-excessive, five membered rings typified by pyrrole, furan and thiophen, and TC-deficient six-membered rings typified by pyridine. The 7i-excessive heterocycles are usually extremely reactive towards electrophilic attack and, with the exception of thiophen, do not exhibit the chemical inertness often associated with aromatic benzene derivatives. Conversely, the TT-deficient heterocycles are extremely inert with respect to electrophilic attack. Paradoxically, it is the high reactivity of the five-membered rings and the inertness of the six-membered rings that give rise to common synthetic problems. The usual methods for the... 

These structures suggest that the carbons in pyridine are partially positively charged (due to the electron-withdrawing effect of the nitrogen) and, therefore, are expected to be deactivated (relative to benzene) toward reaction with electrophiles. Note that the positive charge is distributed between carbons 2, 4, and 6. Therefore, these carbons should be less reactive toward electrophiles than carbon 3 (or 5). 

The 1,3-azoles are not very reactive towards electrophilic attack due to the deactivating effect of the pyridine-like nitrogen. However, electron-donating groups can facilitate electrophilic attack, as in the preparation of oxazoles 3.34 and 3.35. Dimethylamino oxazole 3.33 is essentially functioning like an enamine in this reaction. 

The presence of a pyridine-like nitrogen in the 1,2-azoles makes them markedly less reactive towards electrophilic substitution than furan, pyrrole, and thiophene. (The same effect was noted for the 1,3-azoles in Chapter 3.) Nevertheless, electrophilic substitution is known in 1,2-azoles, occurring principally at the C4 position. This selectivity is reminiscent of pyridine chemistry where the position meta to the electronegative nitrogen atom is the least deactivated (see Chapter 5). 

Since there are no extensive studies on the relative aromaticity of the heterocycles covered in this chapter, the relative order of aromaticity of these systems has been gleaned from disparate studies. A priori, the combined effects of the 7i-electron-deficient five-membered heterocycles annelated to a pyridine nucleus provides a series of bicyclic heterocycles with low reactivity towards electrophiles. In the presence of suitable leaving groups, they are prone to undergo nucleophilic substitution. Since these heterocycles are readily obtained from either appropriately substituted pyridines or five-membered heterocycles, methods for direct functionalization of the parent heterocycles are not frequently studied. Based on the diversity of reactions these heterocycles undergo, it can be inferred that the pyridofuroxans are the least aromatic. 

Pyridines are less reactive toward electrophilic substitution than are the corresponding benzenoid compounds because of the electron-withdrawing inductive (-/) and mesomeric (-M) effects of the ring nitrogen. These effects place substantial positive charge on the 2- and 4-carbon atoms (9.14), which are therefore considerably less reactive than the car-... 

Moreover, as has been recognized, pyridine is strongly hydrogen bonded in protolytic media (hence, for example, its high water solubility). Such hydrogen bonding substantially reduces the reactivity toward electrophiles, and as a consequence reactivity parameters determined for the free base in solution in H-donor solvents differ markedly from those determined in the gas phase. This difference is —0.3 ct units at each position. 

The NMR of pyrrole is slightly less convincing as the two types of proton on the ring resonate at higher field (6.5 and 6.2 p.p.m.) than those of benzene or pyridine but they still fall in the aromatic rather than the alkene region. Pyrrole is also more reactive towards electrophiles than benzene or... 

An equally serious problem is that the nitrogen lone pair is basic and a reasonably good nucleophile—this is the basis for its role as a nucleophilic catalyst in acylations. The normal reagents for electrophilic substitution reactions, such as nitration, are acidic. Treatment of pyridine with the usual mixture of HN03 and H2SO4 merely protonates the nitrogen atom. Pyridine itself is not very reactive towards electrophiles the pyridinium ion is totally unreactive. 

Pyridines with two, and diazines with three strongly activating substituents, are very reactive toward electrophilic substitution. 

Pyridine is only brominated, nitrated or sulfonated under vigorous conditions (Scheme 4.24) with reaction occurring at the least deactivated 3-position. Pyridine does not undergo Friedel-Crafts alkylation or acylation. In many cases the electrophile attacks the nitrogen first to form a pyridinium salt, which is even less reactive towards electrophiles. 

The same electronegativity of nitrogen that makes pyridine unreactive toward electrophilic substitution makes pyridine highly reactive toward nucleophilic substitution. 

Problem 31.16 Pyridine N-oxides not only are reactive toward electrophilic substitution, but also seem to be reactive toward nucleophilic substitution, particularly at the 2- and 4-positions. For example, treatment of 4-nitropyridine N-oxide with hydro-bromic acid gives 4-bromopyridine N-oxide. How do you account for this reactivity and orientation ... 

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